FOXP3 O‐GlcNAcylation Controls Regulatory T Cell Homeostasis and Suppressive Function

Abstract

Regulatory T (Treg) cells are a distinct lineage of T lymphocytes that control immunological self‐tolerance and homeostasis. The use of Treg cells for immunotherapy has been challenging, partially because of the functional heterogeneity and instability of Treg cells. The transcription factor FOXP3 is crucial for Treg lineage specification during development and is continuously required for the suppressive function of mature Treg cells. FOXP3 can be regulated by various post‐translational modifications, which enable transient regulation of FOXP3 functionality in response to environmental cues. Here, we investigate the novel O‐linked N‐Acetylglucosamine (O‐GlcNAc) modification on FOXP3 in Treg cell function and stability.Protein O‐GlcNAcylation is enriched in induced Treg cells, compared to naïve T cells. Chemical augmentation of O‐GlcNAcylation promotes the induction of Treg cell signature genes. O‐GlcNAcylation, controlled by O‐GlcNAc cycling enzymes O‐GlcNAc transferase (OGT) and O‐GlcNAcase (OGA), modifies and stabilizes FOXP3 by counteracting with ubiquitination. Treg cell‐specific OGT deletion in mice does not affect Treg cell lineage specification, but results in fewer suppressive effector Treg cells and the development of an aggressive autoimmune syndrome. O‐GlcNAc‐deficient Treg cells show reduced FOXP3 protein expression and increased effector T‐cell signatures. In summary, we demonstrate that protein O‐GlcNAcylation, by modulating FOXP3, is indispensable for Treg cell suppressive function and lineage stability. Manipulating O‐GlcNAc levels may represent a novel approach to translate Treg cell immunotherapy into clinical practice.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.